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Mucosal immunity of GI tract.pptx
- 1. By- Jaspreet Kaur Assistant Professor Lovely Professional University Mucosal immunity of Gastrointestinal tract
- 2. Introduction â«GI tract has unique characteristic of being the largest organ exposed to external antigens â«multifunctional and serves as a mucosal barrier, an absorptive surface, and a site of active immunity to foreign antigens â« GI tract requires precise regulation to balance immune reactions against foreign antigens while fostering the symbiotic, commensal microbiota.
- 3. â«Structure cells and function of GI tract
- 4. Organization of GI immune tissue
- 6. Mucosal immune system can be further divided into 1. The effector arm â« phagocytes that engulf and kill microbes; cytotoxic T cells, B cells, helper T cells 2. The inductive arm â« are organized lymphoid structures that bring together naive T cells, B cells, and antigen-presenting cells â« specialized lymphoid structures: â«PPs in small intestine â«structurally similar lymphoid tissues in the rectum â«smaller ILFs â«cryptopatches (precursor to intestinal lymphoid follicles) scattered throughout intestine
- 7. Innate immunity in gastrointestinal tract âąIntestinal epithelial cells (IEC) âąAntimicrobial peptides âąToll-like and NOD-like receptors âąIntestinal microbiome âąInnate immune cells
- 8. IEC regulation of barrier function â«largest of the body's mucosal surfaces, covering ~400 m2 of surface area with a single layer of cells organized into crypts and villi â«This surface is continually renewed by pluripotent intestinal epithelial stem cells that reside in the base of crypts â«The proliferation, differentiation and functional potential of epithelial cell progenitors is regulated by the local stem cell niche Nature review; Intestinal epithelial cells. Vol14, 2014
- 9. IEC regulation of barrier function â«Secretory IECs, including enteroendocrine cells, goblet cells and Paneth cells- maintaining digestive or barrier function â«luminal secretion of mucins and antimicrobial proteins (AMPs) by goblet cells and Paneth cells â«establishes a physical and biochemical barrier to microbial contact with the epithelial surface and underlying immune cells Nature review; Intestinal epithelial cells. Vol14, 2014
- 10. IEC anatomy â«Extracellular components â«Intracellular components Nature review Immunol. Intestinal mucosal barrier function in health and disease, 2009
- 11. Extracellular components of IEC barrier Mucin â«A family of heavily glycosylated proteins that are secreted as large aggregates by mucous epithelial cells â«create a barrier that prevents large particles, including most bacteria Unstirred layer â«A thin layer of fluid at epithelial cell surfaces that is separated from the mixing forces created by luminal flow and, in the intestine, peristalsis â«protected from convective mixing forces, the diffusion of ions and small solutes is slowed â«slows nutrient absorption by reducing the rate Nature review Immunol. Intestinal mucosal barrier function in health and disease, 2009
- 12. Cellular components of IEC barrier â«In the presence of an intact epithelial cell layer, the paracellular pathway between cells must be sealed. â«This function is mediated by the apical junctional complex, which is composed of the tight junction and subjacent adherens junction â«supported by supported by a dense perijunictional ring of actin and myosin Nature reviews Immunol. Intestinal mucosal barrier function in health and disease, 2009
- 13. Antimicrobial peptides â«First protective barrier in mucous layer of esophagus: mucin-2 and glycoprotein â«TFF (Trefoil factors) produced by goblet cells: protease-resistant peptides +promote cell survival and migration â«IL-1,IL-4,IL-6,IL-9,IL-13, TNF, type 1 IFN, neutrophil products, microbial adhesive proteinsï increase mucin gene expression Middleton 8 edition; gastrointestinal mucosal immunology t C hellular and Molecular Immunology, 8th Edition
- 14. Defensin families â«Defensins: peptides exert lethal toxic effects on microbes by causing loss of integrity of their outer phospholipid membrane 1. α-defensin: Human neutrophil peptides 1-6, human α-defensin (HD), cryptidins â«HD 5-6 major defensins in small bowel 2. ÎČ-defensin: Human ÎČ âdefensins 1-4 3. Cathelicidins Cellular and Molecular Immunology, 8th Edition Middleton 8th edition; gastrointestinal mucosal immunology
- 15. Toll-like and NOD-like receptors â«Pattern recognition receptors (PRRs) â«PRRs recognize pathogen-associated molecular patterns (PAMPs) such as â«lipopolysaccharide â«flagellin â«bacterial DNA and RNA â«PRRs fall into three families â«Toll-like receptors (TLRs) â«NOD-like receptors (NLRs) â«retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) Nature reviews Immuno; Role of the gut microbiota in immunity and inflammatory disease. Vol13. 2013
- 16. Toll-like receptors â«Role of TLR in GI 1. Sensing bacteria in intestinal epithelium 2. Sensing intestinal injury 3. Regulate barrier function Nature reviews Immunoll; Toll-like receptor signalling in the intestinal epithelium. Vol 10. 2010
- 17. NOD like receptors (NLRs) â«Nucleotide-binding oligomerization domain-containging protein: NOD1, NOD2 â«Intracellular innate immune proteins â«enable detection of intracellular bacteria â«promote clearance through autophagy Nature reviews Immuno; NOD proteins. Vol 14 2014
- 18. Autophagy â«a cytoplasmic bulk degradation system â«which cytoplasmic cargo is targeted and sequestered in double-membrane vesicles, leading to subsequent fusion with the lysosome â«essential for the response to starvation because it facilitates the recycling of cellular components â«can be targeted to intracellular bacteria to restrict their growth Nature reviews Immuno; NOD proteins. Vol 14 2014
- 19. Role of NOD in GI tract 1 Regulation of intestinal barrier function 2 Regulation of immune homeostasis in the gut 3 Regulation of the microbiota Nature reviews Immuno; NOD proteins. Vol 14 2014
- 20. Intestinal microbiome â«Symbiotic relationship â«4 phyla predominate in colon: Firmicutes, Bacteroides, Actinobacteria, Proteobacteria â«Alteration = dysbiosis â«from local/systemic allergy, autoimmunity â«associate with distinct pattern Middleton 8th edition; gastrointestinal mucosal immunology
- 21. Current understanding of the role of gut microbiota 1. Development of intestinal immune system 2. Protection from infection 3. Protection or induction of IBD 4. Extra-intestinal disease Nature reviews Immuno; Role of the gut microbiota in immunity and inflammatory disease. Vol13. 2013
- 22. Innate immune cells â«Eosinophils â«Mast cells â«ILC and multifunctional IgA+ plasma cells â«Macrophages
- 23. Eosinophils â«Esophagus: none â«Duodenum: 9.6±5.3 â«Lower GI tract: ileum 12.4±5.4, ascending colon 20.3±8.2 â«Cecum and rectosigmoid: highest number â«Surface and crypt epithelium: rarely â«The function in non-diseased GI tract-unknown â«recruit to sites of continual cell turnover, regulate local immunity and tissue repair Middleton 8th edition; gastrointestinal mucosal immunology
- 24. Adaptive immunity âąFunctional anatomy of adaptive immunity in GI tract âąHumoral immunity âąCell-mediated immunity
- 25. Functional anatomy of adaptive immunity â« Initiated in collections of lymphocytes and APC closely associated with the mucosal epithelial lining of bowel and in mesenteric LN â« Gut-associated lymphoid tissues adjacent to mucosal epithelium referred to as GALT â«most prominent GALT are Peyer's patches, found mainly in distal ileum or isolated follicles in appendix and colon Cellular and Molecular Immunology, 8th Edition
- 26. Lymphoid site of immune response â«GALT â«Mesenteric LN â«Lingual and palatine tonsils-sites of immune response in oral cavity Cellular and Molecular Immunology, 8th Edition
- 27. Antigen uptake major pathway of antigen delivery from lumen to GALT is through specialized cells (M) cells - found in small bowel epithelium overlying Peyerâs patchs and lamina propria lymphoid follicles M cells have shorter villi M cells engage in transport of microbes or molecules across barrier into GALT, where they are handed off to dendritic cells Cellular and Molecular Immunology, 8th Edition
- 28. Antigen presentation â«APCs in the GI tract include â«professional APCs such as DCs, B cells, macrophages â«nonprofessional APCs such as epithelial cells Middleton 8th edition; gastrointestinal mucosal immunology
- 29. Humoral immunity â«Major function is to neutralize luminal microbes â«mediated mainly by IgA produced in the GALT â«IgA is produced in larger amounts than any other antibody isotype Cellular and Molecular Immunology, 8th Edition
- 30. IgA transport IgA ï form dimer (held together with J chain) ï binds to the poly-Ig receptor at base of an epithelial cellï transported across Cellular and Molecular Immunology, 8th Edition released into lumen by proteolytic cleavage The process of transport called transcytosis
- 31. Cell-mediated immunity â«T cells scattered throughout lamina propria and submucosa and within Peyerâs patches â«Different subsets of effector T cells â«Th17 cell â«Th 2 cells Cellular and Molecular Immunology, 8th Edition
- 32. Thank you